The transformative nature of our research lies in the detailed study of cell-to-cell communication through direct exchange of small RNA species, including regulatory microRNA. For the past twenty years we have studied the biology of human mesenchymal stem cells and have engineered them to become delivery vehicles to secrete transgene protein products for receptor-mediated uptake by surrounding cells in a damaged tissue or by distant cells through systemic protein production. However in the past two years we have developed new as-yet unpublished data showing that direct transfer of RNA species can occur from the MSC to target cells through direct cell-to- cell communication. Through the use of advanced videomicroscopy and molecular techniques we have determined that this cell-contact-dependent intercellular transfer does not occur through small gap junctions but rather through exosomal transport and direct shuttle of small RNA species through tunneling nanotubules. Mesenchymal stem cells are known to respond rapidly to a damaged, hypoxic or inflamed microenvironment and to support the growth, survival and differentiation of other cell types, including hematopoietic stem cells, cells of the vasculature, neurons and others. This phenomenon has been thought to be almost entirely due to the secretion of extracellular proteins. In contrast, we hypothesize that the control of the fate of target cells by MSC can be also mediated through direct transfer of RNA species. We hypothesize that direct transfer of microRNA from human MSC to target cells is a common mechanism for modulating tissue repair and increasing target cell survival at sites of injury. Our planned studies will use our established xenotransplantation wound model systems to explore this novel, unconventional, and potentially paradigm-shifting hypothesis. PUBLIC HEALTH RELEVANCE: Mesenchymal stem cells/stromal cells (MSC) in many tissues can rescue other cells from damage and death. Our new research shows that they can also influence target cell fate through the direct transfer of small RNA species. Our multidisciplinary research focuses on MSC-mediated microRNA transfer mechanisms and impact on differentiation and repair of target cells including hematopoietic stem cells, cells of the vasculature, and neurons. There is direct relevance to a broad range of diseases.